An evolving concern with levodopa therapy relates to its association with elevated homocysteine (HC) levels. Since the late 1990s, several studies have indicated that levodopa dose correlates with elevation of HC. Postuma and Lang (131) reviewed this literature, and the relevance of the increase of HC to PD and patient health remains unclear. The concern relates to data suggesting that elevated HC levels increase the risk of stroke, coronary artery disease, and dementia (132-134). HC is metabolized from dietary methionine through two intermediates: SAM (s-adenosylmethionine) and SAH (s-adenosylhomocysteine). HC is metabolized back to methionine via methylene tetrahydrofolate reductase (MTHFR) or to cysteine via other mechanisms. These enzymatic reactions occur in the presence of folate and vitamins B12 and B6. Hence, deficiency of any of these could lead to elevated HC. This is true for the presence of the C677T MTHFR polymorphism, which decreases metabolism of HC. In PD, it is the conversion of levodopa to 3-OMD via COMT that drives the formation of HC. SAM is the methyl donor for this reaction yielding SAH that is rapidly converted to HC (131). The resulting elevation of HC is generally modest. One study (135) demonstrated after 110 days an increase of 8.2 p,mol/L. Another study indicated that the increase was modest and did not elevate HC to levels beyond the normal range and therefore may not be of concern (136). It has been demonstrated that an increase of 5 |jmol increases the risk of stroke by 65% and ischemic heart disease by 42% (137). However, studies of the risk of stroke in PD have not consistently demonstrated an increased risk. In fact, two studies were positive, four negative, and three others showed a reverse association (131). Rogers et al. (138) suggested that PD patients only in the higher quartile of HC levels had a higher prevalence of coronary heart disease. In contrast, one study showed that the measure of biomarkers for endothelial function in PD patients with modestly elevated HC was normal (139). Hence, the impact of HC changes in PD patients regarding atherosclerotic disease remains to be discerned.
The finding that elevated HC is associated with Alzheimer's disease and vascular dementia might suggest an association with dementia in PD. Zoccolella et al. (140) compared HC levels in 14 PD patients with cognitive dysfunction to 21 patients without cognitive dysfunction, all receiving chronic levodopa therapy. HC levels were significantly higher in the group with cognitive dysfunction versus the non-demented group (21.2 p,mol/L vs. 15.8). There was a correlation between cognitive dysfunction and HC levels. Another study (136) demonstrated that patients with higher HC levels performed more poorly on cognitive and depression measures. These findings are preliminary and require confirmation.
Potential mechanisms of action of HC in its deleterious effects include free radical formation, excitotoxicity, and inflammation, all relevant to PD progression (131).
The relation between disease progression and HC level also warrants further study. Whether PD patients treated with levodopa require supplementation with vitamins B6, B12, and folate or with COMT inhibitors to prevent elevation of HC levels still needs to be studied. Three small trials with the COMT inhibitor entacapone have demonstrated that its use prevents the elevation of HC to some extent (141-143). The impact of this effect on the health of PD patients will require the completion of a long-term prospective trial. A final finding is that elevated HC levels may be associated with the development of osteoporosis and secondary fractures. One study examined 199 women with PD and found that patients with the highest quartile level of HC were at greater risk for hip fractures (144). These results warrant further examination.
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